This invention relates to methods of using a combination of rapamycin and picibanil for the treatment of transplantable carcinogenic tumors.
Rapamycin is an antifungal antibiotic described by C. Vezina et al., J. Antibiot., 28, 721 (1975),, S. N. Sehgal et al., J. Antibiot., 28, 727 (1975), S. N. Sehgal et al., U.S. Pat. No. 3,929,992, issued Dec. 30, 1975 and S. N. Sehgal et al., U.S. Pat. No. 3,993,749, issued Nov. 23, 1976. The latter two patents are herein incorporated by reference. Rapamycin is extracted from a streptomycete (Streptomyces hydroscopicus) isolated from an Easter Island soil sample and is particularly effective against Candida albicans both in vitro and in vivo, H. A. Baker et al., J. Antibiot., 31, 539 (1978). A report by R. R. Martel et al., Can. J. Physiol., 55, 48 (1977) describes the use of rapamycin for the prevention of the development of experimental immunopathies. Recently, rapamycin was shown to be an effective agent for treating carcinogenic tumors in a mammal by S. N. Sehgal and C. Vezina, U.S. patent application Ser. No. 957,626, filed Nov. 3, 1978, herein incorporated by reference. In Belgium, a corresponding application of the latter application issued as Belgium Pat. No. 877,700 on Jan. 14, 1980.
Picibanil (also referred to under the code names, OK-432 and PC-B-45) is an anti-malignant tumor agent with the distinctive feature of potentiating host defense functions against malignancy. Picibanil is produced by incubating the culture of the low virulent Su strain of type III, group A Streptococcus pyrogenes of human origin in Bernheimer's Basal Medium with added penicillin G potassium followed by lyophilization of the incubation mixture, T. Aoki et al., J. Natl. Cancer Inst., 56, 687 (1976); H. Okamota et al., U.S. Pat. No. 3,477,914, issued Nov. 11, 1969, and T. Kono et al., U.S. Pat. No. 3,632,746, issued Jan. 4, 1972. In addition to its use as a single agent for the treatment of some tumors, picibanil has been reported to have been combined with other anticancer agents. The following reports are illustrative thereof, I. Kimura, Gan-to-Kagaku-Ryaho (Cancer and Chemotherapy), 2, 21 (1975); T. Hattori, J. Japan Soc. Cancer Therapy, 9, 381 (1974); I. Kimura et al., Gan-no-Rinsho (Japan J. Cancer Clin.) 18, 886 (1972); and Host Defense Stimulator, Anti-Tumor Str. Pyogenes Preparation, PICIBANIL (OK-432), 1975, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
The combination of rapamycin with picibanil for the treatment of transplantable tumors is novel. The combination of the agents affords a much more effective form of antitumor therapy than that provided by giving the agents alone.